气候变化领域集成服务门户(CCPortal): Regulation of longevity by depolarization-induced activation of PLC-β-IP3R signaling in neurons

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DOI	10.1073/pnas.2004253118
	Regulation of longevity by depolarization-induced activation of PLC-β-IP3R signaling in neurons
	Wong C.-O.; Karagas N.E.; Jung J.; Wang Q.; Rousseau M.A.; Chao Y.; Insolera R.; Soppina P.; Collins C.A.; Zhou Y.; Hancock J.F.; Zhu M.X.; Venkatachalam K.
发表日期	2021
ISSN	00278424
卷号	118 期号:16
英文摘要	Mitochondrial ATP production is a well-known regulator of neuronal excitability. The reciprocal influence of plasma-membrane potential on ATP production, however, remains poorly understood. Here, we describe a mechanism by which depolarized neurons elevate the somatic ATP/ADP ratio in Drosophila glutamatergic neurons. We show that depolarization increased phospholipase-Cβ (PLC-β) activity by promoting the association of the enzyme with its phosphoinositide substrate. Augmented PLC-β activity led to greater release of endoplasmic reticulum Ca2+ via the inositol trisphosphate receptor (IP3R), increased mitochondrial Ca2+ uptake, and promoted ATP synthesis. Perturbations that decoupled membrane potential from this mode of ATP synthesis led to untrammeled PLC-β-IP3R activation and a dramatic shortening of Drosophila lifespan. Upon investigating the underlying mechanisms, we found that increased sequestration of Ca2+ into endolysosomes was an intermediary in the regulation of lifespan by IP3Rs. Manipulations that either lowered PLC-β/IP3R abundance or attenuated endolysosomal Ca2+ overload restored animal longevity. Collectively, our findings demonstrate that depolarization-dependent regulation of PLC-β-IP3R signaling is required for modulation of the ATP/ADP ratio in healthy glutamatergic neurons, whereas hyperactivation of this axis in chronically depolarized glutamatergic neurons shortens animal lifespan by promoting endolysosomal Ca2+ overload. © This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
英文关键词	Aging; ER Ca2+ signaling; Longevity; Lysosomes; Neuronal excitability
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179808
作者单位	Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Sciences Center, Houston, TX 77030, United States; Department of Biological Sciences, Rutgers University, Newark, NJ 07102, United States; Graduate Program in Biochemistry and Cell Biology, MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, United States; Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, United States
推荐引用方式 GB/T 7714	Wong C.-O.,Karagas N.E.,Jung J.,et al. Regulation of longevity by depolarization-induced activation of PLC-β-IP3R signaling in neurons[J],2021,118(16).
APA	Wong C.-O..,Karagas N.E..,Jung J..,Wang Q..,Rousseau M.A..,...&Venkatachalam K..(2021).Regulation of longevity by depolarization-induced activation of PLC-β-IP3R signaling in neurons.Proceedings of the National Academy of Sciences of the United States of America,118(16).
MLA	Wong C.-O.,et al."Regulation of longevity by depolarization-induced activation of PLC-β-IP3R signaling in neurons".Proceedings of the National Academy of Sciences of the United States of America 118.16(2021).